Ulysses Ribeiro

Operative Versus Nonoperative Treatment for Stage 0 Distal Rectal Cancer Following Chemoradiation Therapy Long-term Results

Objective:Report overall long-term results of stage 0 rectal cancer following neoadjuvant chemoradiation and compare long-term results between operative and nonoperative treatment. Methods:Two-hundred sixty-five patients with distal rectal adenocarcinoma considered resectable were treated by neoadjuvant chemoradiation (CRT) with 5-FU, Leucovorin and 5040 cGy. Patients with incomplete clinical response were referred to radical surgical resection. Patients with incomplete clinical response treated by surgery resulting in stage p0 were compared to patients with complete clinical response treated by nonoperative treatment. Statistical analysis was performed using χ2, Student t test and Kaplan-Meier curves. Results:Overall and disease-free 10-year survival rates were 97.7% and 84%. In 71 patients (26.8%) complete clinical response was observed following CRT (Observation group). Twenty-two patients (8.3%) showed incomplete clinical response and pT0N0M0 resected specimens (Resection group). There were no differences between patients demographics and tumors characteristics between groups. In the Resection group, 9 definitive colostomies and 7 diverting temporary ileostomies were performed. Mean follow-up was 57.3 months in Observation Group and 48 months in Resection Group. There were 3 systemic recurrences in each group and 2 endorectal recurrences in Observation Group. Two patients in the Resection group died of the disease. Five-year overall and disease-free survival rates were 88% and 83%, respectively, in Resection Group and 100% and 92% in Observation Group. Conclusions:Stage 0 rectal cancer disease is associated with excellent long-term results irrespective of treatment strategy. Surgical resection may not lead to improved outcome in this situation and may be associated with high rates of temporary or definitive stoma construction and unnecessary morbidity and mortality rates.

SOX2 is an amplified lineage-survival oncogene in lung and esophageal squamous cell carcinomas

Lineage-survival oncogenes are activated by somatic DNA alterations in cancers arising from the cell lineages in which these genes play a role in normal development. Here we show that a peak of genomic amplification on chromosome 3q26.33 found in squamous cell carcinomas (SCCs) of the lung and esophagus contains the transcription factor gene SOX2, which is mutated in hereditary human esophageal malformations, is necessary for normal esophageal squamous development, promotes differentiation and proliferation of basal tracheal cells and cooperates in induction of pluripotent stem cells. SOX2 expression is required for proliferation and anchorage-independent growth of lung and esophageal cell lines, as shown by RNA interference experiments. Furthermore, ectopic expression of SOX2 here cooperated with FOXE1 or FGFR2 to transform immortalized tracheobronchial epithelial cells. SOX2-driven tumors show expression of markers of both squamous differentiation and pluripotency. These characteristics identify SOX2 as a lineage-survival oncogene in lung and esophageal SCC.

Transfusion Requirements in Surgical Oncology Patients A Prospective, Randomized Controlled Trial

Background:Several studies have indicated that a restrictive erythrocyte transfusion strategy is as safe as a liberal one in critically ill patients, but there is no clear evidence to support the superiority of any perioperative transfusion strategy in patients with cancer. Methods:In a randomized, controlled, parallel-group, double-blind (patients and outcome assessors) superiority trial in the intensive care unit of a tertiary oncology hospital, the authors evaluated whether a restrictive strategy of erythrocyte transfusion (transfusion when hemoglobin concentration <7 g/dl) was superior to a liberal one (transfusion when hemoglobin concentration <9 g/dl) for reducing mortality and severe clinical complications among patients having major cancer surgery. All adult patients with cancer having major abdominal surgery who required postoperative intensive care were included and randomly allocated to treatment with the liberal or the restrictive erythrocyte transfusion strategy. The primary outcome was a composite endpoint of mortality and morbidity. Results:A total of 198 patients were included as follows: 101 in the restrictive group and 97 in the liberal group. The primary composite endpoint occurred in 19.6% (95% CI, 12.9 to 28.6%) of patients in the liberal-strategy group and in 35.6% (27.0 to 45.4%) of patients in the restrictive-strategy group (P = 0.012). Compared with the restrictive strategy, the liberal transfusion strategy was associated with an absolute risk reduction for the composite outcome of 16% (3.8 to 28.2%) and a number needed to treat of 6.2 (3.5 to 26.5). Conclusion:A liberal erythrocyte transfusion strategy with a hemoglobin trigger of 9 g/dl was associated with fewer major postoperative complications in patients having major cancer surgery compared with a restrictive strategy.

Gastric Stump Cancer: What Is the Risk?

Patients who have undergone partial gastric resections are at an increased risk for the development of cancer in the gastric remnant. The overall risk increases over time and is higher in patients with an initial diagnosis of gastric rather than duodenal ulcer, in men and following partial gastrectomy with Billroth II reconstruction. The site of tumor growth is predominantly in the anastomotic area, but may occur anywhere in the stump. Enterogastric reflux, achlorhydria, bacteria overgrowth, and Helicobacter pylori appear to be the major factors involved in the etiopathogenesis of the gastric stump cancer. Surveillance of these patients with endoscopy and multiple biopsies may provide the means to diagnose tumors at an early stage, but the cost-benefit ratio of surveillance requires further study. Despite the magnitude of alterations in gastric stump mucosa, unfortunately, at this time we do not have good predictors of patients who will develop a cancer.

Expression of p53, PCNA, and C-erbB-2 in Barrett's metaplasia and adenocarcinoma

We sought to determine if an immunohistochemicalpanel of p53, PCNA, and c-erbB-2 was a useful biomarkerof transformation in Barretts metaplasia. P53, PCNA,and c-erbB-2 immunohistochemistry was performed on resected Barretts specimens selected toshow discrete grades of dysplasia and then onprospectively obtained biopsies. In resection specimens,p53 was positive in 36% with no dysplasia, in 30% with low-grade dysplasia, in 85% with high-gradedysplasia, and in 90% of adenocarcinomas. While anevaluation of proliferation throughout the specimen didnot differ between groups, surface proliferation was significantly higher in high-grade dysplasiathan in low-grade or no dysplasia. All high-gradedysplasia specimens were positive for at least onemarker, compared to 44% with no or low-grade dysplasia. C-erbB-2 was only seen in 31% with high-gradedysplasia and in 10% of adenocarcinomas. Prospectively,the panel had a sensitivity of 100%, a specificity of81% and an overall accuracy of 83% in identifying patients who developed high-grade dysplasia orcancer. Thus, overexpression of p53 occurs early in themalignant transformation of Barretts and increases withhistologic progression, and proliferation at the surface of Barretts epitheliumincreases with progressive grades of dysplasia. Animmunohistochemical panel of p53 and PCNA is a usefulbiomarker for Barretts metaplasia.

Prognostic significance of intraperitoneal free cancer cells obtained by laparoscopic peritoneal lavage in patients with gastric cancer

Laparoscopy is a safe and useful method for examining the local extent and regional spread of disease in patients with gastric cancer. Peritoneal dissemination remains a frequent type of recurrence after surgical treatment. The aim of this study was to determine the prognostic value of intraperitoneal free cancer cells (IFCCs) detected by laparoscopic peritoneal lavage. Forty-nine patients with advanced gastric cancer underwent laparoscopy with cytologic examination for staging. Peritoneal lavage was performed when ascites was not present. Aspirated fluid from the peritoneal cavity was centrifuged and subjected to cytologic examination using Giemsa and Papanicolaou staining methods. Patients were surgically treated and followed for a minimum of 5 years. IFCCs were detected in 41% of the patients. In eight cases (16.3 %) laparoscopy revealed carcinomatosis and/or multiple liver metastases, so laparotomy was not performed. Patterns of recurrence after curative resection included the following: peritoneal (n = 3), local (n = 4), liver (n = 1), and other (n = 1). All patients who tested positive for IFCCs had peritoneal recurrence. The absence of IFCCs was associated with improved overall survival (2 1 months for a 95% confidence interval of 7.4 to 34.6 vs 4 months for a 95% confidence interval of 2.4 to 5.6). Overall survival adjusted for type of resection also demonstrated a favorable outcome for patients who were negative for IFCCs. The following conclusions were drawn: (1) laparoscopic peritoneal lavage cytology may be useful in identifying patients at high risk for peritoneal relapses and may alter treatment, and (2) IFCCs provide additional prognostic information in patients with gastric cancer.

Role of Nutrition Support During Induction Chemoradiation Therapy in Esophageal Cancer

BACKGROUND Preoperative chemoradiation therapy (CRT) potentially benefits a subgroup of patients with esophageal cancer. The ability to administer aggressive CRT may depend on the initial nutritional status and the ability to sustain nutrition during therapy. Parenteral nutrition support during CRT may lead to complications that limit its usefulness and negate any potential benefit. METHODS Data were analyzed to evaluate the role of parenteral nutrition support (PNS) in patients receiving CRT. Forty-five consecutive patients with locoregional esophageal cancer, enrolled in a phase I/II trial of induction CRT, were analyzed. On the basis of the nutrition support received, two groups were defined as follows: group I (with PNS, n = 30) and group II (without PNS, n = 15). Results were compared in terms of chemotherapy (CT) dose tolerated, morbidity of CRT, response rates, and surgical outcome in groups with and without PNS. RESULTS The two groups were comparable for demographic data, stage and site of disease, and performance status. There was no significant difference between the groups in the nutritional parameters (weight and serum albumin) before and after CRT. Group I patients received significantly more (% of total calculated dose) CT compared with group II (5-fluorouracil [5-FU], 86.4% vs 68.8%, p = .02; cisplatin [CDDP], 90.8% vs 78.2%, p = .05; and interferon alpha-2b [IFN-alpha], 95.4% vs 79.8%, p = .05, in groups I and II, respectively). Major (grade III/IV) adverse effects of CT were hematologic (group I, 93.3% vs group II, 86.6%, p = .59) and gastrointestinal (group I, 56.67% vs group II, 33.3%, p = .2). Postsurgical staging revealed complete response in 10 (22%) and a major response in 23 (51%) patients, although the response rates were similar in the two groups (group I, 76.6% vs group II, 66.6%, p = .8). Surgical morbidity (51.8% vs 61.5%, p = .73), mortality (7.4% vs 7.6%, p = 1.00), and hospital stay (22.5 vs 19.6 days, p = .63) were also similar in the two groups. CONCLUSIONS PNS can be provided to these patients without an increased risk of CRT or resection-related morbidity. Although early and prolonged PNS facilitates administration of complete CRT doses, no benefit is derived from the administration of more CRT in the present regimen. The utility of PNS in this setting is unclear and, until further clarified, should not be applied routinely to this cohort of patients.

Relationship Between Persistence of Helicobacter pylori and Dysplasia, Intestinal Metaplasia, Atrophy, Inflammation, and Cell Proliferation Following Partial Gastrectomy

Helicobacter pylori and partial gastricresection are risk factors for gastric cancer. Our aimswere to investigate the presence of H. pylori inpostgastrectomy patients and to correlate that withalterations in mucosal architecture and cell proliferation.One hundred fifty-one endoscopic biopsies from 22patients, (15-47 years of age, mean 29.2 years)following partial gastrectomy with Billroth IIreconstruction for peptic ulcer disease, were examined for thepresence of H. pylori using Giemsa staining. Sectionswere scored for grade of hyperplasia, intestinalmetaplasia, dysplasia, inflammation, and atrophy.Immunohistochemistry for proliferative cell nuclear antigen (PCNA)was used to characterize cell proliferation. H. pyloriwas observed in 17/22 (77.3%) of patients or in 57/151(37.7%) of biopsies. Metaplasia was seen in 18/22, chronic atrophic gastritis in 20/22, and cysticglandular dilation in 21/22 patients. The highest typeof metaplasia in each patient was: four Type I, fiveType IIA and nine Type IIB. Dysplasia was present in 16 biopsies from nine patients. H. pyloriwas more prevalent in intestinal metaplasia type I(44.8% of biopsies), than in type IIA (32.7%) or typeIIB (25%). No H. pylori was detected in regions showing dysplasia or cystic glandular dilation. H.pylori colonization was associated with degree ofinflammation (P = 0.00001) and cell proliferation (P =0.0001). In conclusion, H. pylori is commonly seen many years after gastrectomy, it is associated withan increased epithelial cell proliferation, and it isnot present in areas of histologic markers ofpremalignancy (type IIB metaplasia anddysplasia).

Interleukin-2-activated natural killer cells may have a direct role in the control of Leishmania (Leishmania) amazonensis promastigote and macrophage infection.

To study the role of Natural Killer (NK) cells in Leishmania infection, peritoneal macrophages from BALB/c mice were infected with Leishmania (Leishmania) amazonensis promastigotes and incubated with interleukin‐2 (IL‐2)‐activated NK (A‐NK) cells at different ratios of A‐NK cells to infected macrophages (5:1, 1:1, 0.2:1). The A‐NK cells were added either together with the parasites (0‐h group) or 24 h later (24‐h group). Morphological studies of the cultures revealed predominance of parasitic debris within macrophages that were in close contact with A‐NK cells and the decrease in parasite recovery was directly proportional to the A‐NK cell concentration used. Interferon‐γ (IFN‐γ) and IL‐12 were detected in the supernatant at levels proportional to the A‐NK cell concentration used. No significant difference was observed between the groups with respect to NO levels in the culture supernatant. When A‐NK cells were added directly to the L. (L.) amazonensis promastigote cultures, the parasite recovery decreased proportional to the number of A‐NK cells added. In vivo studies demonstrated smaller lesion sizes in animals inoculated with both parasites and A‐NK cells compared with parasites alone. Histopathology of the skin lesions from animals receiving A‐NK cells together with the parasites showed moderate parasitism and a nodular inflammatory infiltrate formed by mononuclear cells and a few vacuolized macrophages. In contrast, animals inoculated only with the parasites showed a highly parasitized dermis with infiltration of intensely vacuolized macrophages. These results demonstrate the role of A‐NK cells in parasite lysis and in resistance of macrophages to L. (L.) amazonensis in the early phase of infection.

Microsatellite instability in solitary and sporadic gastric cancer

UNLABELLED Recently, the presence of microsatellite instability (MSI) has been reported in gastric cancer and associated with older age of presentation, distal tumor location, early disease staging, and better overall prognosis. Different characteristics in presentation and in tumor behavior may be explained by different genetic alterations during carcinogenesis of gastric cancer. Identification of specific genetic pathways in gastric cancer may have direct impact on prognosis and selection of treatment strategies. PATIENTS AND METHODS All 24 patients were treated by radical surgery. Fragments of normal and tumor tissues were extracted from the specimen and stored at -80 degrees C before DNA purification and extraction. PCR amplification utilizing microsatellite markers was performed. Tumors presenting PCR products of abnormal sizes were considered positive for microsatellite instability (MSI+). RESULTS Five patients (21%) had tumors that were MSI+ in at least 1 marker. In the group of patients with Laurens intestinal-type gastric carcinoma, 3 had tumors that were MSI+ (23%), while in the group of diffuse-type gastric cancer, 2 patients had tumors that were MSI+ (19%). The mean age of presentation and the male:female ratio was similar in both groups. Tumors that were MSI+ were more frequently located in proximal portion of the stomach compared to microsatellite-stable (MSS) tumors (40% vs. 16%). Although there was a trend of patients with MSI+ tumors towards a proximal gastric tumor location, early staging, and negative lymph node metastasis, there was no statistical significance compared to those with MSS tumors (P >.1). Comparison of overall and disease-free survival between gastric tumors that were MSI+ and those that were MSS found no statistically significant differences (P >.1). CONCLUSIONS Microsatellite instability is a frequent event in gastric carcinogenesis and shows a trend towards distinct clinical and pathological characteristics of gastric cancer.